The field of genetic testing is relatively young but is rapidly becoming one of the most important new areas of modern medicine. It’s been over 20 years since the first human genetic code was sequenced, which took a decade of development and cost over a billion dollars. Since then, the cost of DNA sequencing has rapidly declined, and we are now learning about the genetics of human biology and its impact on disease at an accelerating pace. Two of the biggest surprises to me of the last decade of research are that 1) human genetic variation is much greater than expected, and 2) genetic disorders are both more common and complex in the human population than previously thought. Despite this complexity, enormous gains have been made. Genetic testing is beginning to play a significant role in the diagnosis and treatment of disease across virtually all areas of medicine. This includes cancer, heart disease, neurological disorders, and pediatric diseases.
Genetic variation in the human population is much greater than previously thought
Ten years ago, a clinical-grade DNA sequence for a single disease-causing gene cost as much as $3,000 (and there are approximately 20,000 genes in the genome). Today’s clinical laboratories can simultaneously sequence hundreds, and even thousands, of genes for a few hundred dollars, a fraction of the cost of just one gene a decade ago. With the decrease in cost, DNA testing is rapidly moving from basic research into clinical medicine and the race is on to look at genetics in the broader context of human disease. Soon, we will be able to sequence the entire genome at high resolution to identify all known genetic variants at a reasonable cost. (Low resolution, research-grade whole genome sequencing is already available but misses many of the most complex variant types required for clinical medicine.)
It was originally thought that there would be a “normal” healthy genome that all other genomes could be compared to and that each mutation was abnormal and might cause disease. We now know that there is tremendous genetic variation within the human population, and only a fraction of those variants cause disease. No single person’s genome can be defined as the gold standard, “normal” genome. We share most of our genetic code, but each of us is unique. There are approximately 20,000 genes that code for proteins in the human genome, and most genes contain thousands of variants across different individuals. As there are over seven billion people in the world and only a small portion have ever had their DNA sequenced, we are still in the very early stages of cataloging all of the variants and the impact they have on biology and disease.
The process of DNA replication within our cells is amazingly accurate, with numerous editing mechanisms that correct mistakes during cell division or embryo development. Nonetheless, the editing process is not perfect: each newborn child will differ from its parents in about 30-40 “letters” in the genome, on average. Those small changes can cause genetic disorders, but they also create genetic diversity that may be important for survival of the species and are a natural part of the evolutionary process. Most variants will be silent in terms of any biological effect. Some variants will cause disease, and some will have positive effects that may protect from disease. All of that genetic diversity is rapidly being uncovered. You can think of these 20,000 protein encoding genes as a symphony with many different instruments. If one player deviates slightly from the norm, it might go unnoticed. However, a dramatic change could ruin the whole concert!
Genetic disorders are much more common than previously thought
There are many thousands of inherited genetic conditions that have been identified as being caused by specific genes with known genetic variants, and more are being discovered every year. Until recently, it was thought that only a few percent (1-5%) of the population might have a genetic condition. More recent studies suggest that as many as 20% of individuals have a known genetic mutation that may affect their health in a significant way over the course of their lifetime. Proactive clinical genetic testing of healthy individuals is now ongoing in commercial clinical labs and academic research. Early data from several thousand patients in a study conducted by my former company, Invitae shows that approximately 7% of the study population had a clinically actionable mutation, just in genes causing cancer or cardiovascular disease—two leading causes of death. When expanded to a set of about 140 genes, as much as 16% of the population had a common clinically actionable mutation across a spectrum of conditions. If this data holds up across larger studies, as many as 50 million people in the US may have a clinically actionable genetic variant that could lead to preventive care! In addition, the majority of the population carries a mutation for one of over a thousand recessive disorders (those in which both parents must carry the same genetic disorder for the child to be affected). And importantly, everyone carries genetic variation that will affect how we metabolize and respond to certain medicines. In aggregate, rare genetic disorders are actually quite common! Everyone’s genetic code has a significant impact on their health, susceptibility to disease, and response to medications.
Human genetics is significantly more complex than previously thought
One of the very first clinical applications of genetics was the diagnosis of sickle cell anemia which is caused by a single mutation in the hemoglobin gene. One gene, one mutation, one disease—simple. The cystic fibrosis gene, on the other hand, has over a thousand different disease-causing variants with a range of outcomes, from extremely severe to mild, depending on the variant. One gene, one disease, but thousands of different mutations with varying outcomes! Within the last decade over a hundred genes that cause multiple types of hereditary cancer have been identified with often thousands of mutations per gene. Hundreds of genes, dozens of cancer types, hundreds of thousands of mutations! BRCA2 alone has over 10,000 different mutations that have been cataloged in public databases with varying effects on protein function.
The coming era of genomic medicine will be both exciting and challenging for all people as we uncover the code of life and understand more about what makes us human.
Not only is the genome complex, it’s also “messy” with many unusual complex variant types that must be interpreted clinically. A single letter change is the most common but larger deletions, insertions, inversions, repeats, and copy number variants also represent a disproportionate share of pathogenic mutations. For example, there are estimated to be almost as many pseudogenes in the genome as functioning genes. Pseudogenes are genomic “fossils,” genes that are carried along in the genome but no longer code for functioning proteins (although they may have other functions). A mutation in a pseudogene may be mistaken for a mutation in the active gene and must be resolved to determine if the mutation is harmless or life-threatening. The most common genetic cause of death in newborns, spinal muscular atrophy, has exactly that type of problem and requires special clinical analysis.
In part, because of its complexity, genetic testing is a very misunderstood field today. Knowledge of genetics, for many consumers, has been defined by DNA tests for ancestry that sometimes provide a modest amount of health information. While consumer DNA tests can help inform us of our ancestry, they are not always useful for understanding medical conditions. The majority of consumer DNA tests look at a relatively small number of simple common variants (such as three well-characterized BRCA mutations for breast cancer that are found almost exclusively in the Ashkenazi Jewish population). Unfortunately, some of the most common genetic disorders also have a high prevalence of very complex, difficult to sequence variants (pseudogenes are just one example) that require much more sophisticated sequencing and analysis techniques. One can think of the typical consumer genetic test as a very low resolution scan of Earth from high altitude that shows where cities are located. Clinical genetic tests, then, correlate to a very high resolution Google street map with all of the detail included. While consumer DNA tests can be informative at times and can find some common simple variants causing disease, they miss the vast majority of variants that are clinically important to medical diagnosis and treatment. Fortunately, as costs have come down, high-resolution clinical tests are now available for a few hundred dollars from multiple clinical labs that are comparable to the cost of a consumer genetic test.
Genetics is personal
In the late 1990s my oldest sister’s newborn granddaughter was diagnosed with a rare genetic disease called galactosemia. Galactosemia is caused when both copies of a gene involved in metabolizing galactose (a common sugar found in many foods) are defective. If you inherit one faulty gene, you will still produce enough of the enzyme made by the gene to function normally. If you inherit two bad copies, the disease can be extremely severe. Within days to weeks, the child may have severe and permanent intellectual disability. Some children die within the first months of life. Fortunately my grandniece was diagnosed promptly and the treatment is straightforward: galactose must be eliminated from the diet for life. For me, it was the first realization that virtually all individuals and all families carry risk for genetic conditions. I, too, carry the gene for galactosemia, as do some of my children. But now we know it is important to do carrier screening in advance to be prepared for these types of recessive disorders.
A number of years later, my nephew died of a sudden heart attack at the age of 27. It turns out that he had a genetic mutation for hypertrophic cardiomyopathy—a common cause of sudden cardiac death in young people. Because he was adopted, no one knew about his family history, which later revealed a long family trend toward early cardiac events. My sister now shares her story of loss in her role as an advocate for genetic testing.
While consumer DNA tests can be informative at times and can find some common simple variants causing disease, they miss the vast majority of variants that are clinically important to medical diagnosis and treatment.
Historically genetic testing was expensive and, therefore, restricted to patients who had serious symptoms or had a significant family history of a genetic condition. Now that genetic testing costs are coming down, we are seeing a slow shift toward more proactive genetic testing. Family history is often inaccurate or unknown and thus not that reliable. In the future we will be able to screen for many genetic events long before they happen—and hopefully alleviate enormous human suffering from unexpected genetic conditions.
What good is a genetic diagnosis if you can’t do anything about it?
Enormous progress is being made in developing therapeutics for genetic diseases, and hope is rapidly emerging everywhere. New technologies for gene therapy and gene editing as well as the development of traditional therapies targeting specific genetic disorders bring new hope that, perhaps, no disease is incurable.
For example, epilepsy is the most frequent chronic neurologic condition in children. About half of cases are caused by genetic mutations, and an increasing number of those cases have potential therapies. There are over 100 different genes involved in epilepsy. All can now be tested simultaneously at very high resolution for a few hundred dollars.
CLN2 deficiency is one such rare epilepsy disorder. Seizures are one of the first symptoms, but the disease quickly moves into a more serious neurological disorder. Children with CLN2 deficiency are often completely normal for the first 2-3 years of life but then begin to develop seizures followed by the loss of neuromuscular function. Most children don’t survive to their teenage years. Imagine your healthy, loving, two year old beginning to lose all function, and there is nothing you can do. Except, now you can! A drug for CLN2 deficiency is available that stops the progression of the disease, but only if the disease is diagnosed promptly at the onset of symptoms.
Another interesting example is a more common disease called hemochromatosis. Hemochromatosis is an iron storage disorder that results in iron toxicity that builds slowly over the course of a lifetime. The disease presents as a large number of common conditions like chronic fatigue, obesity, diabetes, inflammatory bowel syndrome, heart disease, depression, and mental illness. As a result, hemochromatosis is rarely diagnosed correctly until years after the onset of symptoms. Yet, about 10% of the population of European descent are carriers for the gene that causes this disease. As a carrier, most have no symptoms, but it means there are a fairly large number of individuals who are homozygous (two bad copies of the genes). Of those individuals, about 20% will go on to develop serious clinical symptoms of disease. The treatment for hemochromatosis is simple. Giving blood frequently reduces the amount of iron and can restore normal iron levels over time. Unfortunately, many are diagnosed too late, after damage has already been done.
The real power of genetics is to identify disease before it happens. The future of genetic testing could allow us to screen every child at birth for all known clinically-actionable genetic disorders and to manage that information over the course of their lifetime. Imagine the day in which we have potential therapeutic treatments for all known genetic conditions. That day may be closer than you think!
As a Christian and a scientist I am constantly amazed by the incredible complexity, beauty, and sophistication of human biology, but also challenged by the suffering for many patients with one of the thousands of genetic disorders. The coming era of genomic medicine will be both exciting and challenging for all people as we uncover the code of life and understand more about what makes us human. To some, understanding the molecular basis for life and disease may challenge their concept of God as creator. To me, it simply reveals it and demonstrates clearly how we are all members of the same family and yet all unique in God’s eyes: in personality, in spirit, and in our genes! As always, technology has the power for good and for evil. Using genomics to alleviate suffering and human disease for all, even the poorest of communities and sickest of individuals, is a noble and important calling.
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